The Development and Application of Ligand-Gated Split-Kinases to Interrogate Signal Transduction of Src Family Kinases
AuthorStankavich, Brittany Marie
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PublisherThe University of Arizona.
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EmbargoRelease after 08/15/2024
AbstractProtein kinases participate in complex signal transduction pathways to regulate virtually all cellular processes from cell growth to cell death. Aberrant kinase activity can lead to the development and progression of numerous diseases including cancer, and therefore has emerged as leading drug targets for therapies. Traditional methods for elucidating kinase function have relied on genetic approaches that either overexpress or silence kinase activity; however, these methods lack temporal control. Moreover, kinase inhibition using pharmacological small-molecules lacks specificity due to the highly conserved catalytic domain, and infer function through loss of function as opposed to gain of function. Given the dynamic nature of phosphorylation and dephosphorylation, it is useful to design tools for selective activation of protein kinases in order to dissect their individual cellular roles. Towards this goal, we describe a strategy for direct activation of kinases using chemical inducers of dimerization (CID), which allows for simultaneous, temporal control over multiple kinases in a system. This method consists of deliberately separating a kinase into two inactive fragments that are then attached to an interacting protein pair. Upon addition of a small molecule CID, the interacting protein pair dimerize causing the kinase fragments to reassemble into a functional ternary complex. A major focus of this dissertation describes the application of this strategy to interrogate cellular signalingpathways of Src and Src family kinases.
Degree ProgramGraduate College